Characterization of the modulatory effect of zeaxanthin isolated from maize kernels on cellular signaling pathways associated with hyperglycemia-induced HepG2 cell proliferation

Background: Carotenoids are the group of antioxidant phytonutrients, found to repress carcinogenesis by
modulating multiple cellular signaling pathways. Since diabetes patients have two to three folds increased risk of
liver cancer, the present study aimed to explore the role of zeaxanthin on various molecular targets of high
glucose-mediated human hepatocellular carcinoma (HepG2) cell proliferation.
Methods: The antiproliferative effect of zeaxanthin was examined by WST-1 assay. The DCFH-DA fluorescence
dye was used to measure the intracellular ROS levels. The modulatory effect of zeaxanthin on the protein
expression of MAPK-p38, Akt, and ERK, and antioxidant markers such as Nrf2, SOD2, HO1, and catalase, and
apoptosis markers, Bcl2, P53, and cleaved caspase 3 was measured by western blotting. Apoptosis-inducing effect
of zeaxanthin in high glucose subjected HepG2 cells was examined using DAPI staining.
Results: Zeaxanthin exhibits an effective growth inhibition in high glucose subjected HepG2 cells. It drastically
repressed high glucose-mediated elevation of ROS levels. Further, zeaxanthin suppressed hyperglycemiamediated
ROS-driven p38 activation to mitigate HepG2 cell proliferation. Zeaxanthin also switched on the
apoptosis pathway in hyperglycemic HepG2 cells. The apoptosis induction by zeaxanthin was confirmed with
downregulated Bcl2 and P53 and upregulated cleaved caspase 3 protein expression.
Conclusions: The current findings substantiate the previous findings that zeaxanthin has greater potential than
lutein in sensitizing hyperglycemic HepG2 cells by modulating multiple signaling pathways. The study highlights
the importance of zeaxanthin as a powerful phytonutrient which possesses chemotherapeutic potential against
diabetes-associated liver cancer progression.